Sublingual or buccal pharmaceutical composition

ABSTRACT

The invention relates to a sublingual or buccal pharmaceutical composition comprising trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz 2,3:6,7!oxepino- 4,5-c!pyrrole or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable auxiliaries suitable for use in sublingual or buccal compositions, and the use thereof for the manufacture of a sublingual or buccal pharmaceutical composition for the treatment of mental disorders, such as psychosis and schizophrenia.

This application is a 371 of PCT/EP95/00765, filed Mar. 1, 1995.

The invention relates to a sublingual or buccal pharmaceuticalcomposition, and more specifically to a sublingual or buccal compositionfor the treatment of various mental disorders.

The compound trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz2,3:6,7!oxepino 4,5-c!pyrrole and the preparation thereof are disclosedin U.S. Pat. No. 4,145,434. The compound is described as havingCNS-depressant activity and antihistamine and antiserotonin activities.

The pharmacological profile oftrans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz 2,3:6,7!oxepino4,5-c!pyrrole, its kinetics and metabolism, as well as the first safetyand efficacy studies in human volunteers and in schizophrenic patientswere reviewed by De Boer et al. (Drugs of the Future 1993, 18(12),1117-1123). It has been established that Org 52225-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz 2,3:6,7!oxepino4,5-c!pyrrole maleate (1:1)! is a very potent dopamine and serotoninantagonist with potential antipsychotic activity.

Phase I clinical studies on the effects of perorally administeredtrans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz 2,3:6,7!oxepino4,5-c!pyrrole however, revealed that serious cardiotoxic effects, e.g.postural hypotension and/or impairment of baroreceptor functioning,occurred.

Surprisingly, it has now been found that on sublingual or buccaladministration, trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz2,3:6,7!oxepino 4,5-c!pyrrole has substantially less cardiovascular sideeffects.

The invention therefore relates to a sublingual or buccal pharmaceuticalcomposition comprisingtrans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz- 2,3:6,7!oxepino4,5-c!pyrrole or a pharmaceutically acceptable salt thereof, andpharmaceutically acceptable auxiliaries suitable for use in sublingualor buccal compositions.

The compositions of the invention are useful in treating mammals,including humans, suffering from diseases which are susceptible totreatment by trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz2,3:6,7!oxepino 4,5-c!pyrrole. Such diseases include mental disorders,such as tension, excitation, anxiety, psychosis, and schizophrenia. Thecompositions may also be used for antihistamine and for antiserotoninrelated diseases.

In its simplest form the pharmaceutical composition of the inventionconsists of an aqueous solution, for instance comprising 0.9% (w/v) ofsodium chloride and the active compound5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz 2,3:6,7!oxepino4,5-c!pyrrole, or a pharmaceutically acceptable salt thereof. Themaleate salt (Org 5222) is a preferred salt. The active compound israpidly absorbed from these aqueous pharmaceutical compositions, whenkept under the tongue or in the mouth of a patient.

Preferred pharmaceutical compositions are solid pharmaceuticalcompositions which rapidly disintegrate in the mouth of a subject, uponinsertion into the buccal pouch or upon placement under the tongue.Rapid disintegration means that the pharmaceutical composition isdisintegrated within 30 seconds in water at 37° C., and preferablywithin 10 seconds, as measured according to the procedure described inRemington's Pharmaceutical Sciences, 18th Edition (Ed. A. R. Genaro),1990, pp 1640-1641; see also US Pharmacopeia, Chapter <701>.

In a preferred embodiment the pharmaceutical compositions of theinvention are tablets or lozenges which comprise a rapidlydisintegrating composition of a pharmaceutically acceptablewater-soluble or water-dispersable carrier material. Tablets andlozenges comprising a rapidly disintegrating composition of apharmaceutically acceptable water-soluble or water-dispersable carriermaterial are known in the art, for example as disclosed in U.S. Pat. No.4,371,516. Such tablets may be prepared by freeze-drying of an aqueoussolution comprising 5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz2,3:6,7!oxepino 4,5-c!pyrrole, a water-soluble or water-dispersablecarrier material and, optionally, pharmaceutically acceptableexcipients. Such excipients are known in the art, see for instanceRemington's Pharmaceutical Sciences, 18th Edition (Ed. A. R. Genaro),1990, pp 1635-1638, and are commonly used in pharmaceuticalcompositions, for instance surfactants, colouring agents, flavouringagents, preservatives and the like.

The water-soluble or water-dispersable carrier material is preferablywater-soluble. Suitable water-soluble carrier materials are(poly)saccharides like hydrolysed dextran, dextrin, mannitol, andalginates, or mixtures thereof, or mixtures thereof with other carriermaterials like polyvinylalcohol, polyvinylpyrrolidine and water-solublecellulose derivatives, like hydroxypropyl cellulose.

A preferred carrier material is gelatin, especially partially hydrolysedgelatin. The partially hydrolysed gelatin can be prepared by heating ofa solution of gelatin in water, for example in an autoclave at about120° C. for up to 2 hours. The hydrolysed gelatin is used inconcentrations of about 1 to 6% (w/v), and preferably in concentrationsof about 2 to 4% (w/v).

The preferred dosage forms of the composition of the invention, i.e.tablets or lozenges, can be prepared by methods known in the art. Forexample, according to a method as disclosed in British Patent 2,111,423,an aqueous composition comprising a predetermined amount of5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz- 2,3:6,7!oxepino4,5-c!pyrrole, a pharmaceutically acceptable water-soluble orwater-dispersable carrier material and optionally pharmaceuticallyacceptable auxiliaries and excepients, is transferred into a mould,after which the composition is frozen and the solvent is sublimed,preferably by freeze-drying. The composition preferably contains asurfactant, for example Tween 80 (polyoxyethylene (20) sorbitanmono-oleate), which may help to prevent the freeze-dried product fromsticking to the surface of the mould.

The mould may comprise a series of cylindrical or other shapedepressions, each having a size corresponding to the desired size of thedosage form. Alternatively, the mould may have a larger size than thedesired size of the dosage form, and after the contents are freeze-driedthe product can be cut into the desired size. Preferably the dosage formis freeze-dried in the form of a lyosphere, which is a freeze-driedspherical-shaped droplet containing the active ingredient.

A preferred mould would correspond to a depression in a sheet of filmmaterial, as for example disclosed in U.S. Pat. No. 4,305,502 and U.S.Pat. No. 5,046,618. The film material may be similar to that employed inconventional blister packs.

Each dosage form of the pharmaceutical composition of the presentinvention comprises one dosage unit of5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz- 2,3:6,7!oxepino4,5-c!pyrrole as active ingredient. A dosage unit may contain between0.005 mg and 15 mg of the active ingredient. Preferably the dosage unitcontains 0.03-0.50 mg of5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz 2,3:6,7!oxepino4,5-c!pyrrole.

The invention further relates to the use oftrans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz- 2,3:6,7!oxepino4,5-c!pyrrole for the manufacture of a sublingual or buccalpharmaceutical composition for treating mental disorders, such aspsychosis and schizophrenia.

A method of providing therapy using the pharmaceutical composition ofthe present invention comprises the insertion of a dosage form accordingto this invention in the buccal pouch or under the tongue of a subject,such as a human. The ultimate dosage to provide relief for the patientdepends, apart from individual characteristics, on the patient's weight,condition and age. Usually, administration of 1-4 dosage units of thepharmaceutical composition of the invention per day is sufficient forobtaining a therapeutic effect. The therapy may be continued as long asnecessary or desired.

The invention is further illustrated by the following examples.

EXAMPLE 1

a: Preparation of Hydrolysed Gelatin (3% w/v)

Gelatin (30 g) was dissolved in 1 l of distilled water under heating andconstant stirring. The resulting solution was autoclaved at 121° C. (10⁵Pa) for one hour, upon which the solution was allowed to cool to roomtemperature to give hydrolysed gelatin (3% w/v).

b: Preparation of a Solid Pharmaceutical Dosage Form

A sheet of polyvinyl chloride (PVC) containing cylindrical depressionswas cooled with solid carbon dioxide. 0.2 g of Org 52225-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz 2,3:6,7!oxepino4,5-c!pyrrole maleate (1:1)! were dissolved in 1 l of hydrolysed gelatinunder mixing. While mixing was continued, in each of the depressions 0.5ml of the solution were placed. When the contents of the depressionswere frozen, the PVC sheet was placed in a freeze-drying system. Analuminum foil was finally sealed to the sheet so as to close off thedepressions containing the freeze-dried pharmaceutical dosage forms.Each depression contains a pharmaceutical unit dosage comprising 0.10 mgof 5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz 2,3:6,7!oxepino4,5-c!pyrrole maleate (1:1).

Examples 2

In a manner as described in Example 1b a pharmaceutical composition wasprepared comprising:

0.2 g of 5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz2,3:6,7!oxepino 4,5-c!pyrrole maleate (1:1) (Org 5222), 0.50 g of Tween80 (polyoxyethylene (20) sorbitan mono-oleate, 30 g of sucrose and 1 lof hydrolysed gelatin (3% w/v).

Example 3

In a manner as described in Example 1b a pharmaceutical composition wasprepared comprising:

2 g of 5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz 2,3:6,7!oxepino4,5-c!pyrrole maleate (1:1) (Org 5222), 0.50 g of Tween 80(polyoxyethylene (20) sorbitan mono-oleate, 30 g of sucrose and 1 l ofhydrolysed gelatin (3% w/v), 1 l of hydrolysed gelatin (3% w/v).

Example 4

A pharmaceutical composition was prepared comprising:

0.2 g of 5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz2,3:6,7!oxepino 4,5-c!pyrrole maleate (1:1) (Org 5222), 17 g of sodiumalginate, 35 g of dextran (MW approx. 40.000), 17.5 g of dextrose, anddistilled water to a volume of 1 l, which composition was freeze-driedinto unit dosage forms.

Example 5

A pharmaceutical composition was prepared comprising:

0.4 g of 5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz2,3:6,7!oxepino 4,5-c!pyrrole maleate (1:1) (Org 5222), 50 g of dextrin,0.20 g of Tween 80 (polyoxyethylene (20) sorbitan mono-oleate, 30 g ofpolyvinylpyrrolidine and distilled water to a volume of 1 l, whichcomposition was freeze-dried into unit dosage forms.

Example 6

Lyospheres were prepared by dissolving 138.9 g of sucrose, 40.8 g ofsodium citrate, and 111 mg of polysorbate 20 in 300 ml of distilledwater, adjusting the pH to 7 using 1N hydrochloric acid and 1N sodiumhydroxide and adding water to 500 ml. The solution was homogenized bystirring and filtered through a sterile 0.22 μm filter, after which thesolution was freezed into droplets of 0.1 ml, which droplets weretransferred in the frozen state into a freeze dryer and thenfreeze-dried to unloaded spherical lyophilized dosage units(lyospheres).

120 mg of 5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz2,3:6,7!oxepino 4,5-c!pyrrole maleate (1:1) (Org 5222) were dissolved in1 ml of ethanol and 83 μl of this solution were added to one lyospheres,after which the ethanol was removed by gentle heating, to obtain alyosphere containing 10 mg of Org 5222. Lyospheres containing 1 and 0.1mg of Org 5222 respectively, were prepared in a similar manner bydissolving 60 or 6 mg of Org 5222 respectively in 1 ml of ethanol, afterwhich 16.6 μl of this solution were added to one lyosphere.

Example 7

A pharmaceutical composition was prepared comprising:

0.094 g of 5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz2,3:6,7!oxepino 4,5-c!pyrrole maleate (1:1) (Org 5222), 30 g ofmannitol, 40 g of gelatine, and distilled water to a volume of 1 l,which composition was freeze-dried according to the method of Example 1binto unit dosage forms, each of which comprises 10 μg of Org 5222.

Example 8

Orthostatic hypotension (tilt challenge) and direct haemodynamic andelectrophysiologic effects were determined as follows:

Method

Beagle dogs (10-20 kg, Harlan, France) were instrumented underanesthesia. A micromanometer (Konigsberg Instruments) was placed intothe aorta near the aortic arch and another in the left ventricle. A pairof segment length piezoelectric crystals (Triton Technology) weresutured into the endocardial left ventricular wall at a distance ofapproximately 1 cm from each other. All connecting wires were tunneledsubcutaneously and exteriorized at the back of the neck. Two weekspostoperatively the dogs were placed in a Pavlov-stand and transducersconnected to an eight-channel recorder (Gould ES3000). Anelectrocardiogram (standard lead II) was also recorded usingconventional bipolar limb leads.

Org 5222 (or placebo) was administered either orally (1, 2.5, 5, 10, or50 mg/kg) or sublingually (0.01, 0.1, or 1 mg/kg) to conscious dogs.

Aortic arterial systolic, diastolic and mean blood pressures (mmHg),heart rates (beats/min), ventricular systolic segmental shortenings (mm)and the QT intervals were continuously registered and automaticallyanalysed every 15 minutes during the 5 hour observation period followingOrg 5222 administration. QTc (which reflects cardiac repolarisationtime) was calculated according to Bazett's formula.

Dogs were tilted to the 90° upright position for periods of 30 secondsby lifting their forelimbs. Tilt responses refer to the maximum changesobserved in aortic blood pressure and heart rate during the 30 secondobservation period and were assessed both 30 minutes and just before Org5222 administration and then 15, 30, 60, 90, 120, 180, 240, and 300minutes after administration.

Blood samples were taken just before drug administration and at 15, 30,60, 90, 120, 240, 300, 360 minutes and at 21 hours after administrationin each case just after tilt challenge. To plasma, prepared from theblood samples, internal standard(cis-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz 2,3:6,7!oxepino4,5-c!pyrrole maleate (1:1); Org 5033) was added and Org 5222 andinternal standard were isolated by extracting the alkalinized plasmawith n-hexane. The Org 5222 concentration was determined by capillarygas chromatography (cGC) with NPD-detection.

Results

The hypotensive response to tilt was modestly and dose-dependentlyaugmented by Org 5222, irrespective of the route of administration.However, for equivalent Org 5222 plasma levels, the accompanyingtachycardia was always more marked after oral administration of Org 5222than after sublingual administration (Table 1)

                  TABLE 1                                                         ______________________________________                                        Mean heart rate change due to tilt                                            (corrected for placebo effects), calculated per                               concentration range (ng/ml) and for each of the two                           administration routes, oral (po) and sublingual (sl).                         Org 5222 plasma   Mean heart rate change per                                  concentration     concentration range                                         (ng/ml)           po     sl                                                   ______________________________________                                        0-3               5.7    4.6                                                   3-10             21.3   0.6                                                  10-30             21.1   18.3                                                  30-100           47.8   14.9                                                 100-300           52.8   8.9                                                  ______________________________________                                    

Conclusions

Tachycardia accompanying orthostatic hypotension was more marked afteroral than after sublingual administration of Org 5222. Directhaemodynamic and electro-physiological effects were also less markedafter sublingual than after oral administration with regard to negativeinotropy and QTc prolongation.

Moreover, dogs treated orally showed marked side effects such asexcitation of long duration, whereas dogs treated sublingually showedonly short excitation periods followed by long lasting sedation.

We claim:
 1. A pharmaceutical composition comprising as a medicinallyactive compound: trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz 2,3:6,7!oxepino 4,5-c!pyrrole or apharmaceutically acceptable salt thereof; wherein the composition is asolid composition and disintegrates within 30 seconds in water at 37° C.2. The pharmaceutical composition of claim 1, wherein the compositionfurther comprises a pharmaceutically acceptable water-soluble orwater-dispersable carrier material.
 3. The pharmaceutical composition ofclaim 2, wherein the carrier material is partially hydrolysed gelatin.4. A method for treating tension, excitation, anxiety, and psychotic andschizophrenic disorders, comprising administering sublingually orbuccally an effective amount of a pharmaceutical composition comprisingtrans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz 2,3:6,7!oxepino4,5-c!pyrrole or a pharmaceutically acceptable salt thereof.
 5. Thepharmaceutical composition of claim 1, wherein the compositiondisintegrates within 10 seconds in water at 37° C.
 6. The composition ofclaim 1, further comprising one or more pharmaceutically acceptableauxiliaries selected from the group consisting of hydrolyzed dextran,dextrin, mannitol, algenates, polyvinyl alcohol, polyvinyl pyrrolidineand water soluble cellulose derivatives.
 7. A pharmaceutical compositioncomprising trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz2,3:6,7!oxepino 4,5-c!pyrrole or a pharmaceutically acceptable saltthereof; and pharmaceutically acceptable auxiliaries, wherein thecomposition is made by the process ofa) providing an aqueous solutioncomprising said compound and a water soluble or water dispersablecarrier material; b) transferring the composition of a) into a mold; c)freezing the composition in the mold; and d) subliming the solvent byfreeze-drying.
 8. A pharmaceutical composition comprisingtrans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz 2,3:6,7!oxepino4,5-c!pyrrole maleate, mannitol, and gelatin.
 9. The method of claim 4,wherein the composition is a solid pharmaceutical composition whichrapidly disintegrates in the mouth of a subject upon insertion into thebuccal pouch or upon placement under the tongue.
 10. The method of claim4, wherein the pharmaceutical composition further comprisespharmaceutically acceptable auxiliaries selected from the groupconsisting of hydrolyzed dextran, dextrin, mannitol, algenates,polyvinyl alcohol, polyvinyl pyrrolidine and water soluble cellulosederivatives.
 11. The method of claim 10, wherein the pharmaceuticallyacceptable auxiliary is partially hydrolyzed gelatin.
 12. The method ofclaim 4 wherein the pharmaceutical composition comprisestrans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz 2,3:6,7!oxepino4,5-c!pyrrole maleate, mannitol, and gelatin.
 13. A method for treatingantihistamine and antiserotonin related diseases comprisingadministering sublingually or buccally an effective amount of apharmaceutical composition comprisingtrans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz 2,3:6,7!oxepino4,5-c!pyrrole or a pharmaceutically acceptable salt thereof.